Delivery device for zero-order release of an active principle into a dissolution fluid and process for its preparation

Abstract

A delivery device for zero-order release of an active principle into a dissolution fluid includes a reservoir consisting of a solid matrix of a homogeneous mixture of a polymer material, at least a portion of the active principle and an additive soluble in the dissolution fluid with negative heat of solution, a coating on the solid matrix-type reservoir of a first, release rate-controlling insoluble membrane which modulates the active principle release according to the desired kinetics; and a second, protective membrane on the release rate-controlling membrane of a soluble polymer material.

What is claimed is: 
     
       1. A delivery device which in the presence of a dissolution fluid releases a biologically active principle at a substantially constant rate for an extended period of time, the device comprising (a) a reservoir comprising (i) a solid porous matrix of homogenous polymeric material which material is insoluble and unswellable in the dissolution fluid, the geometric dimensions of which remain substantially unchanged over said period of time;   (ii) an additive which is soluble in the dissolution fluid and which has a negative heat of dissolution with respect to said fluid; and   (iii) the biologically active ingredient, said additive and biologically active ingredient being disposed in the pores of said matrix;     (b) a first homogenous and continuous coating of a film-forming polymer on said reservoir, said coating maintaining a substantially constant surface area and thickness over said period of time, said polymer being insoluble in said dissolution fluid with said coating being permeable to both said fluid and to a solution of said active ingredient in said fluid, the thickness of said first coating being such as to comply substantially with the relationship:   thickness=D×S×C.sub.s /R        in which D is the diffusion constant of said first coating;   S is the surface area of said first coating;   C s  is the saturation constant of the active principle in the dissolution fluid; and   R is the release rate; and     (c) a second homogenous and continuous coating of a a film-forming polymer material which is soluble in the dissolution fluid disposed over said first coating.   
     
     
       2. A device according to claim 1 wherein said reservoir includes a buffer. 
     
     
       3. A device according to claim 2 wherein said buffer constitutes up to about 30% by weight of said matrix. 
     
     
       4. A device according to claim 1 wherein said biologically active principle is present in an amount from about 30 to about 90% of the weight of said reservoir. 
     
     
       5. A device according to claim 1 wherein said additive which is soluble in the dissolution fluid with a negative heat of solution is present in an amount of from about 5 to about 50% of the weight of said reservoir. 
     
     
       6. A device according to claim 5 wherein said additive is a polyol or an acid. 
     
     
       7. A device according to claim 6 wherein said additive in mannitol, dextrose, sorbitol, or xylitol. 
     
     
       8. A device according to claim 1 wherein said matrix constitutes from about 3 to about 20% of said reservoir. 
     
     
       9. A device according to claim 8 wherein the polymeric material of said matrix is cellulose acetate, high viscosity hydroxypropylmethyl cellulose, cellulose acetate propionate, ethyl cellulose, or polymethacrylate. 
     
     
       10. A device according to claim 1 wherein said first homogenous and continuous coating is a vinyl polymer or co-polymer, cellulose, cellulose acetate, hydroxypropylmethyl cellulose, cellulose acetate propionate, ethyl cellulose, an acrylic polymer, or an acrylic co-polymer. 
     
     
       11. A device according to claim 1 wherein said second coating is low viscosity hydroxypropylmethyl cellulose. 
     
     
       12. A device according to claim 1 wherein additional active principle is present in said second polymeric coating. 
     
     
       13. A device according to claim 1 wherein a plasticizer is present in said first coating. 
     
     
       14. A device according to claim 1 wherein said biologically active principle is an orally administerable drug. 
     
     
       15. A device according to claim 14 wherein the outer surface of said reservoir is a biconvex discoid defined by the circular intersection of two opposed spherical segments, the discoid having diameter from 6 to 16 mm, the bending radius of the spherical segments of the biconvex discoid being comprised between 10 and 18 mm, the diameter:thickness ratio of the biconvex discoid being comprised between 2 and 5. 
     
     
       16. A device according to claim 14 wherein said reservoir defines an intermediate cylindrical wall segment and two opposed spherical end segments intersecting said cylindrical wall segment.